RESUMEN
The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT2A/5-HT2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT2 receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism.
Asunto(s)
Fenetilaminas/farmacología , Fenetilaminas/farmacocinética , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacocinética , Anisoles/química , Línea Celular , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Células HEK293 , Alucinógenos/química , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Fenetilaminas/síntesis química , Fenetilaminas/química , Receptor de Serotonina 5-HT2A/genética , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/genética , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.
Asunto(s)
Cognición/efectos de los fármacos , Hipercinesia/psicología , Inhibición Prepulso/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Encéfalo/metabolismo , Catalepsia/inducido químicamente , Estimulantes del Sistema Nervioso Central , Dextroanfetamina , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Femenino , Humanos , Hipercinesia/inducido químicamente , Hipercinesia/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
N-Benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2' and 3'-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2'-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2'-benzyl substituent were also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.